It is known that chemical madiators such as various leukotrienes, thromboxane A2, various prostaglandins and the like, which are generated in the metabolic route of arachidonic acid, cause certain allergy, inflammation, asthma and the like.
Further, it is considered that ill-balances of these chemical mediators induce various disorders and it is practically expected that antagonists of these chemical mediators in arachidonic acid cascade and/or inhibitors of the biosyntyhesis of such mediators are developed as a medicine.
It is elucidated that leukotrienes which are produced through 5-lipoxygenase, have important functions as chemical mediators and especially, leukotrienes C4, D4 and E4 are components of slow-reacting substance of anaphylaxis (SRS-A), being an important mediator of allergic diseases such as bronchial asthma and inflammations.
Accordingly, the compounds which have leukotriene-antagonistic actions are promising in the treatment of allergic diseases such as bronchial asthma and inflammations.
U.S. Pat. Nos. 4,749,701 and 4,902,700, and European Patent Publication No. 206751-A disclose that certain styryl compounds, certain thiazole compounds and certain phenylalkenylquinoline compounds have leukotriene-antagonistic actions and inhibitory actions against synthesis of leukotriene, respectively.
European Patent No. 173516 discloses N-[4-oxo-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-8-yl]-4-(4-phenylbutoxy)-ben zamide as a leukotriene-antagonist.
European Patent No. 137979 discloses that certain diazinyl ethenyl-phenyl oxamic acid compounds have immunological, anti-inflammatory and anti-allergic activity, and U.S. Pat. No. 4,393,075 discloses that 5-lipoxygenase-inhibitory 6-(12-hydroxy-5,10-dodecadiynyl)-2,3,5-trimethyl-1,4-benzoquinone inhibits to synthesis and releases SRS-A and are useful as an anti-allergic agent.
But, only a few drugs having leukotriene or SRS-A antagonistic activity or inhibitory activity against such biosynthesis, especially by oral administration are known and none is practically used.
Moreover, leukotriene B4 (LTB4) is a chemical mediator on various inflammations (e.g. gout), has strong chemotactic actions against human leucocyte and then a relationship between LTB4 and inflammation has been reported. Further, it is said that myocardial infarction takes a bad turn by the aggregation of a lot of leucocytes. Therefore, it is expected that the 5-lipoxygenase inhibitors and inhibitors to biosynthesis of leukotriene B4 can prevent the aggravation of inflammation or myocardial infarction.
As mentioned above, many kinds of the compounds which specifically act as antagonists of various chemical mediators and inhibitors of the enzymes concerning to the biosynthesis of such chemical mediators have been produced, but no compounds are sufficiently applicable to use as medicines.
On the other hand, it is well-known that histamine is a major causing factor for allergy and inflammation. Recently, the chymase (protease of chymotrypsin type) which exists in granulocyte of mastocyte and involves the release of granular histamine through IgE receptor, has been investigated. Accordingly, studies of a new type of anti-allergic agent which inhibits the release of chemical mediator such as histamine leading to inhibition of chymase, have been intensively conducted.
Therefore, it is also desired to develop a single medicine which can regulate multiple chemical mediators, and prevent or treat the allergy, asthma or inflammation.